Cardiovascular Disease (CVD)

Why does insulin resistance (metabolic syndrome) promote the cardiovascular condition?

why?

Infarction

Infarction is the obstruction of the blood supply to an organ or region of tissue causing death of the tissue. => Heart attack if it's obstruction to the coronary artery causing heart tissue death. => Stroke if it's obstruction to the internal carotid artery causing brain tissue death.

Why does inflammation result in more lesions of the arteries?

is it bc it promotes the arteries to become glycosylated, which then they tend to break more often?

Step 3) Intermediate lesion - what feature of this stage should you remember?

***Know that this is the stage when muscle cells infiltrate By this stage, we have an established chronic inflammation. As more LDLs accumulate, macrophages become foam cell and secrete cytokines. Characterized by consistent inflammation.

Framingham Epidemiological Study

**Due to ethical reasons, we cannot do studies where we put humans on high fat diets. We can only record their habits and relate it to outcomes. Many such types of studies are out there. The most famous is the Framingham Epidemiological Study. => A 60 year project "longitudinal" 5000+ ppl study and their progeny => Attempting to correlate various behavioral, dietary, physiological, etc "factors" with a propensity to severe cardiovascular illness *****Know this: We wouldn't have the understanding of CVD we have now if it wasn't for the Framingham Epidemiological Study. This was the first friendly large scale epidemiological study that tries to connect behavior and lifestyle to specific diseases.

Why is high LDL levels a Framingham Risk factor for CVD?

**Studies using mice as model organisms have confirmed this LDLs tend to invade lesions. The more LDLs you have, the more invasion of LDLs you will have. Macrophages try to absorb LDLs by engulfing them. They eventually die by necrosis or apoptosis, spilling the lipids into the plaque core. Theres massive inflammation occurring. And finally the plaque ruptures. A blood clot forms to stop the bleeding. But in atherosclerosis, the artery passage is narrowed and the blot clot can stop the blood flow.

Progression of Atherosclerosis: The early lesion - modified lipoproteins and formation of foam cells

**When the concentrations of LDL is high (when we are obese or high fat diets) [RETENTION] 1) LDLs tend to stick to those lesions and penetrate under the endothelium of the artery. [MODIFICATION] 2) Once inside, these LDLs get oxidized, their lipoproteins are modified, and they trigger "a mild inflammation state". [ACTIVATION] 3) The mild inflammation is sensed by the endothelial cells of the arteries, which they respond by secreting extracellular molecules on their surface signalling inflammation and recruiting immune cells.

Progression of Atherosclerosis

-Initial lesion -Fatty streak -Intermediate lesion -Atheroma -Fibroatheroma -Complicated lesion (rupture) **blood clots accumulate at the rupture to try to repair it

The major reasons for the reduction in cardiovascular deaths in recent years are due to:

1) better/faster surgical intervention & rapid use of clot-dissolving medications 2) blood pressure reducing medications 3) cholesterol reducing medications ***Despite these improvements, we are counteracting these improvements due to our diet and lifestyle like eating chai for breakfast

What are some Framingham Risk factors for CVD?

=> being elderly => cig smoker (*mentioned) => high blood pressure (*mentioned - FDR) => high blood lipids, particularly LDLs (*mentioned) => diabeties or insulin resistance => male => obese, particularly abdominal obesity => having predisposing genes => high markers of inflammation such as C-reacting protein ***These are CORRELATIVE (not causative) evidence

Step 6) Complicated lesion => what causes the rupture of the plaque?

=> presence of platelets appear, which indicates rupture ***The fibrous cap can no longer hold the plaque together, as the necrotic core got too big. Other factors that contribute to rupture of plaque: => macrophages secrete MMPs (matrix metalloproteinases), which are protein cleaving enzymes that contribute to the cleavage of these fibers. This contributes to destabilization of the whole structure.

Step 5) Fibroatheroma

=> which is the strengthening of that fibrous cap => remember the smooth muscle cells have been there since the intermediate lesion (step 3) and they consistently deposit more and more collagen and fibrous mass => in fibroatheroma we have more and more deposition of fibrous collagen and other fibers by smooth muscle cells => smooth muscle cells also ingest LDLs and become foam cells => we also have participation of T-cells that detect inflammation and also secrete their own inflammatory cytokines. => Necrosis of macrophage foam cells and smooth muscle foam cells contributes more extracellular cholesterol to the necrotic core. => Calcium deposits in arteries appear at this stage. Xray can detect these calcium deposits.

Intracerebral atherosclerosis can cause cerebral infarction

Arteries to the brain Internal carotid artery supplies blood flow to the brain. An atherosclerotic plaque can rupture and form a blood clog, stopping blood flow to the brain. That area of the brain can die.

What is atherosclerosis?

Atherosclerosis is the narrowing and hardening of the arteries. It is the major underlying cause of cardiovascular diseases (CVDs).

What does baby aspirin do to help cardiovascular condition?

Baby aspirin is an anticoagulant (it decreases coagulation (the formation of blood clots)). You don't want to take it long term in large doses bc you start bleeding. In low doses, it both decreases the clotting and also decreases inflammation (remember that inflammation is critical in the formation of these initial lesions of the arteries)

Drugs to help treat/prevent cardiovascular disease: blood pressure reducing drug (Anti-hypertensives)

Beta-blockers => ex: propanolol, atenolol => they inhibit beta adrenergic receptors -> reducing the effects of adrenaline -> reducing nerve impulses to heart -> lowering heart rate *Aspirin reduces inflammation

Coronary atherosclerosis can cause myocardial infarction

Blocks blood flow to heart muscle As plaque accumulates, it tends to rupture and blot clots forms, clogging the artery. If this happens in arteries that supply our muscles or other organs, it is not good but it is not deadly. But if blood supply stops to a particular area in the heart, it can result in myocardial infarction.

Progression of Atherosclerosis: Foam cells aggregate

Foam cells aggregate within the developing arterial plaque. LDLs become too much for foam cells to bear. They eventually undergo necrotic death, releasing harmful cellular contents into the plaque (this happens in the Atheroma stage). At this stage you see an accumulation of extracellular lipids and foam cells, and thickening of red blood cells.

Heart disease deaths distribution map

Has a similar distribution to diabetes

High blood pressure can be fatal

High Blood Pressure (hypertension) Stage 2 Systolic >160 mm Hg Diastolic > 100 mm Hg

Which class of lipids are most involved in atherosclerosis?

LDL

Progression of Atherosclerosis: Formation of the atherosclerosis plaque starts with a lesion

Lesions happen all the time and the clotting system of our blood takes care of them. However lesions form more frequently in individuals who have infections. The walls of their arteries become glycosylated and tend to break more often. ***CONNECTION: In diabetics, the high glucose concentration promotes inflammation. (why? bc of ROS (see last cardset, "How obesity leads to diabetes)). How does a lesion in the endothelium lining the arterial lumen start? => Begins with endothelial cell death or damage (due to infection, diabetes, smoking, high blood pressure) => wound signals (cytokines) are released => Wounded endothelium is invaded by monocyte/macrophages (an inflammatory response)

Progression of Atherosclerosis: Lesion progression - inflammation and smooth muscle cells migrate in....formation of fibrous cap INTERMEDIATE LESION

Macrophage foam cells release inflammatory signals, recruiting smooth muscle cells to migrate to this region under the arterial wall, where they secrete extracellular matrix proteins (fibrin, collagen, proteoglycans) that form a fibrous cap of the plaque. At this point we have: => macrophage foam cells => smooth muscle cells => extracellular matrix that strengthen and thicken the plaque

Which cells are most involved in the progression of atherosclerosis?

Macrophages

Progression of Atherosclerosis: Macrophages engulfing oxidized LDLs

Macrophages have scavenger receptors, which interacts with oxidized lipoproteins and engulfs the oxidized LDLs, becoming foam cells. Foam cells are macrophages that engulfed a lot of lipids/LDLs and as a result, have many cytoplasmic lipid droplets. They can persist or can die (apoptosis) bc of the extraordinarily large amount of cholesterol that they contain.

Progression of Atherosclerosis: Monocytes - the first responders

The first responders to this inflammation signal are monocytes. Monocytes are precursors to macrophages. Monocytes are undifferentiated cells that become macrophages when activated during inflammation. [ADHESION] 1) Monocytes bind to these extracellular molecules on the surface of endothelial artery cells, which slows them down (in the blood) [MIGRATION] 2) Then they penetrate into the cell ("they are the surveyors of our immune system") [DIFFERENTIATION] 3) They see oxidized LDLs, which is a signal for them that something is not right, and differentiate into macrophages

Does a plaque cause infarction?

The plaque itself contributed to the thickening of the artery and impaired the blood flow, but it doesn't cause the infarction. What causes infarction and death is thrombus. Thrombus = blood clot Thrombus formed there when the plaque ruptured - some of the lipid rich material of the plaque spilled and the red blood cells and other components of the blood clot accumulated around it, completely blocking the artery and stopping the blood supply to the individual. This causes an infarction.

Consequences of plaque rupture: thrombus

This whole inflammation process promotes blood vessels coming into the plaque. When the plaque ruptures, blood starts spilling out. This attracts platelets to come and to stop the leakage. The rupture results in the exposure of the inner surface of the blood vessel, which contains molecules that initiate coagulation (clotting). Normally this is a good thing bc it stops bleeding. But in this case, it leads to formation of a blood clot and in a condition in which the artery is highly constricted (due to the lipid deposits, foam cells, necrosis, etc), the blood clot can clog the artery and cause an infarction. Plaque rupture exposes blood components to tissue factor, initiating coagulation, the recruitment of platelets, and the formation of a thrombus.

Step 4) Atheroma - what feature of this stage should you remember?

Yellow mass is starting to form (plaque core). What is it made of? => as foam cells continue to take up LDLs, they can no longer hold all the cholesterol and they rupture either by necrosis (uncontrolled cell death) or by apoptosis => this causes the spilling of lipids and necrotic cell products making up the yellow mass ***Know that this is the stage where we have the necrotic core